Process for the manufacture of phosphorus-containing esters



United States Patent 3,041,367 PROCESS FOR THE MANUFACTURE OF PHOS-PHORUS-CONTAINING ESTERS Jean Pierre Leber and Karl Lutz, both of Basel,Switzerland, assignors to Sandoz Ltd, Basel, Switzerland No Drawing.Filed June 19, 1961, Ser. No. 123,346 Claims priority, applicationSwitzerland July 8, 1960 21 Claims. (Cl. 260-461) The present inventionis concerned more especially with the preparation of per seknownphosphorus-containing esters of the formula wherein each of R and Rrepresents an alkyl group with at least one and at most two carbon atoms(i.e. methyl and ethyl), and Y represents an oxygen atom or a sulfuratom, and wherein R may also represent an aliphatic chain interrupted byan oxygen atom (as e.g. -CH CH OC H etc.) or by a sulfur atom (as e.g.--CH2CH2SCH3, etc.). R2 may also represent an aryl radical (as e.g.phenyl, tolyl, etc.), an aralkyl radical (as e.g. benzyl, phenyl-ethyl,etc.) or a heterocyclic radical (as e.g. pyridyl, pyrimidyl, etc.).

The compounds of formula A as above described are known to have valuableinsecticidal activity and have been used inter alia in the preparationof compositions useful in combating aphis and other garden insects aswell as household insects.

A number of processes are known for the preparation of Compounds A. Ofthese, the following are the most important:

(1) The reaction of compounds of the formula R SC H -Hal with salts ofdialkylthiolphosphoric acids or of dialkyldithio-phosphoric acids orwith the corresponding free acids themselves, if necessary in thepresence of a basic acid-binding agent which fixes the hydrogen halideformed.

(2) Replacement of the halogen atoms in compounds of the formula (R O)PYSC H -Hal, in which Hal stands for C1 or for Br and Y stands for O orS, by the radical SR which is derived from a mercaptan HSR (3) Reactionof dialkyl-phosphoric acid halides or dialkylthiophosphoric acid halideswith compounds of the formula R SC H SH in the presence of a basicacidbindihg agent fixing the hydrogen halide formed.

All these prior processes have the drawback that they necessitate themanufacture of intermediate products which are expensive or difiicult tohandle. In particular,

for the simplest of the above processes, i.e. that denoted as (1), it isnecessary first to manufacture compounds of the "formula RgSC H -Hal,which is generally done by esterifying' an alcohol of the formula R SC HOH with gaseous hydrogen chloride or by adding to this alcoholsubstances which liberate hydrogen chloride. This makes it necessary touse a plant which is resistant to the corrosion of this acid. Alsocompounds of the type R S C H -Hal are poisonous. They have an effectsimilar to mustard gas so that persons who come into contact with thesecompounds must take special precautions.

In the second of the above mentioned processes, the intermediate productof the formula is expensive andit must be condensed with a mercaptan ofthe formula HSR a compound which on account of itsa'lmost unbearablesmell is very difficult to handle industrially.

3,041,367 Patented June 26, 1962 ice r; is

The third process necessitates first of all the manu facture of acompound of the formula R SC H Hal the drawbacks of which have alreadybeen described above, since this is necessary for the manufacture of themercaptan of the formula R SC H SH.

The primary purpose of the present invention is the embodiment of aprocess for the manufacture of Compounds A, which process is free of theseveral aforesaid drawbacks of the known processes. This purpose isrealized by' the present invention by the expedient of developing aprocess which does not require the use of compounds of the formulaR2sC2H4-Ha1 and which consequently enables the above detailed prior artdrawbacks to be avoided. According to the present invention, only in thepresence of hydroxyethylalkyl-sulphides and dialkyldithio-phosphoricacids or dialkyl-thiol-phosphoric acids are necessary,-which gives theCompounds A in a single reaction.

The process according to the invenuon for the manufacture of thephosphorus-containing esters of the formula SCH2OH;SR1 (A) ischaracterized in that an acid of the Formula I an acid which can yieldprotons or of a Lewis acid (these acids being denoted as III) and thatthe water is removed as it is formed, R R and Y in the precedingformulae having the afore-enumerated significances.

The process according to the invention is advantageously carried out asfollows. An acid III is added to an alcohol of Formula II at a fairlylow or average temperature, optionally in a suitable solvent such aschlorobenzene, ethylene dichloride, dioxane or a carboxylic aciddialkylamide with lower alkyl groups, as e.g. dimethylformamide.

Then 1 mol of an acid according to Formula I is added all at once orgradually at a low, normal or raised temperature. Here the acid can beused as such or dissolved in a usual solvent. The acid I can also beadded in the form of an alkali metal salt in which case however, in thereaction ofsmixing an alcohol II and an 'acid III a sufficiently strongacid must be added in order to set free the acid I from the salt. Such aprocess can be particularly appropriate if an acid according to FormulaI is used in which Y stands for an oxygen atom.

The order in which the reactants are mixed can be varied. The reactionmixture is stirred at ambient temperature or at a raised temperature andthe water formed during the reaction is removed by theuse of reducedpressure or by azeotropic distillation or by the addition of a strongdehydrating agent; The addition of the dehydrating agent can be made atthe moment when the alcohol 11 is .mixed with the acid Ill. If thedehydratingmgent is a proton or Lewis-acid it is not necessary to addanother acid of this kind as a catalyst.

It is wholly unexpected thatthe esterification'of thiophosphoric acidsor of dithiophosphoric acids with alcohols could be carried out in thisway. Prior workers have reported that in all trials of the directesterification of dialkyldithiophosphoric acids it had not been possibleto make neutral esters. onry's mixture of the alcohol n =1.5330. Yield:64%

and acid was obtained which contained decomposition products of theseparticipants of the reaction.

In order to get higher yields by the process of the present invention,it is advantageous to Work in a solvent, as e.g. amides of carbonic andlow molecular carboxylic acids such as formamide and dimethylformamide,dioxane, sulphuric acid (use of excess of the acid which then acts asthe solvent), xylene or of'an excess of the alco hol Ii, or a mixture ofthe said solvents. The solvent can be recovered partly or completely.

In a preferred embodiment of the invention, each R is ethyl or methyl, Yis O or S, and R is ethyl. Otherwise stated, the preferred compounds ofFormula I are diethyldithiophosphoric acid, dimethyldithiophosphoricacid, diethylthiolphosphoric acid and'dimethylthiolphosphoric acid,while the preferred compound of Formula II, which is preferred interalia because it leads to good yields and to products which can easily bepurified by distillation, is hydroxyethylethylsulphide.

Examples of compounds of Formula III are sulphuric acid,methanesulphonic acid, sulphuric acid anhydride, zinc chloride, etc. Asstrong dehydrating agents, sulphuric acid anhydride, phosphoruspentoxide, and zinc chloride are preferred. It is particularlyadvantageous to use a mixtureof anhydrous sulphuric acid and sulphuricacid anhydride (technical oleum), since this mixture has acid propertiesas well as being a dehydrating agent.

According to the invention, good yields of products are obtained, thesmell of which is considerably less unpleasant than that of the productsmade by the known processes.

The following examples set forth presently preferred embodiments whichillustrate but do not limit the present invention. Yields are given inpercentages calculated on the theoretical yield. Temperatures are givenin degrees centigrade. Percentages are by Weight. Parts by weight bearthe same relationship to parts -'by volume as do grams to milliliters.

. Example 1 3 parts by Weight (0.03 mol) of concentrated sulphuric acidare added to 44 parts by Weight (0.4 mol) of hydroxyethylethylsulphideat to 20. Then 74 parts byweight (0.4 mol) of, diethyldithiophosphoricacid are stirred in dropwise in the course of 4 hours Finally, themixture is Example 2 Example 1 is repeated. However, this time 20 partsby weight (0.2 mol) of concentrated sulphuric acid are used, instead ofthe 3 parts by weight used in Example 1.

A liquid residue of 82 parts by Weight is obtained, the refractive index11 of which is 1.5382 and which is completely distillable under reducedpressure. The main fraction consists of 70 partsbyweight of pure(C2H50)2PS2C2H4SC2H5. Bl at to 106;

of pure product.

Example 3 -32 parts by Weight (0.2 mol) of dimethyldithiophos phoricacid in 40 parts by volume of chlorobenzene are added to a mixture of19.5 parts by weight (0.2'mol) of concentrated sulphuric acid and 22parts by weight (0.2 mol) of hydroxyethylethylsulphide. i

The suspension is rapidly agitated and during 4 hour: at 50 underreduced pressure the azeotrope of chloro benzene and water is distilledofli. (During this period 4 portions, each of 40 parts by volume ofchlorobenzene are added.)

The reaction mixture is then decanted and the chlorobenzene layer iswashed first with aqueous 5% sodium hydroxide solution and then withwater, then it is dried and evaporated.

41 parts by weight of a liquid residue are obtained which have arefractive index a of 1.5503. Paper chromatography of a sample (aspecial quantitative determination which consists of a comparison of thesurface of these zones) shows a content of at least 60% of the compoundof the formula (CH O) PS C H SC H Example 4 20 parts by weight ofconcentrated sulphuric acid are added drop by drop at 0 to 22 parts byweight (0.2 mol) of hydroxyethylethylsulphide parts by volume orc'hlorobenzene. The temperature is then raised to 60 and 37.5 parts byweight 0.2 mol) of diethyldithiophosphoric acid are added. The reactionmixture is stirred at 60 for 3 hours and then washed as in Example 3.After distilling off the chlorobenzene, 32 parts by weight of acolorless liquid are left, the refractive index n of which is 1.5370,and which yields on distillation 23 parts by weight of the pure compound20 parts by weight of concentrated sulphuric acid are added drop by dropat 0 to 10 to 66parts by weight (0.6 mol) of hydroxyethylethylsulphide.Then the temperature is raised to 40 and 37.5 parts by weight (0.2 mol)of diethyldithiophosphoric acid are added drop by drop during 2 hours atthis temperature. Then the reaction mixture is stirred for 1 hour at 40and then for 2 hours at 60. The reaction mixture is then treated asdescribed in Example 1.

57 parts by weight of a liquid are obtained, the refractive index n ofwhich is 1.5348 and which yields after distillation 43 parts by weightof the .pure compound (C H O) PS C H SC H Yield: 78.5% of the pureproduct.

Example 6 phosphorus pentoxide are added, after which the mixture isheated up to 50. After half an hour a further 7 parts by weight ofphosphorus pentoxide are added and the mixture stirred for 4 hours at60. The reaction mixture is then taken up in chloroform and washed asdescribed above. 7 42 parts by weight of a liquid residue are obtained,the refractive index 11 of which is 1.5333, and which yields ondistillation 36.5 .parts by weight of the pure compound (C H O) PS C HSC H 'Yield: 66.6% of pure product. 7

Example 7 l4 parts by weight (0.1 mol) of anhydrous zinc chloride areadded to a mixture of 22 parts by weight (0.2 mol) ofhydroxyethylethylsulphide and 37.5 parts by weight ofdiethyldithiophosphoric acid and then the mixture is stirred for 3-hoursat 60.

The reaction mixture is then treated as in Example I, and afterevaporating off the chloroform, a liquid residue of 45 parts byweightremains, the refractive indexn V v on distillation 39 parts by weight ofthe compound (C H O) PS C H SC H Yield: 71.3% of pure product.

Example 8 24 parts 'by weight (0.3 mol) of sulphuric acid anhydride areadded to 250 parts by volume of dioxane with vigorous stirring at to 10and then 32.5 parts by weight (0.3 mol) of hydroxyethylethylsulphide areadded under the same conditions. A precipitate is formed whichredissolves. Then 56 parts by weight (0.3 mol) ofdiethyldithiophosphoric acid are added during 3 hours at 60. Thereaction mixture is then taken up in a large quantity of water andextracted 3 times with chloroform. The chloroform solution is washedfirst with sodium hydroxide solution and then with water, dried andevaporated. The yellowish liquid residue obtained, weighing 58 parts byweight, has a refractive index n of 1.5362. On distillation, 35 parts byWeight of the pure compound (C H O) PS C H SC H are obtained. Yield:42.6% of pure product.

Example 9 40 .parts by weight (0.5 mol) of sulphuric acid anhydride areadded drop by drop at 10 to to 40 parts .by weight (0.55 mol) ofdimethylformamide. Then 1 partby volume of concentrated sulphuric acidis added, then'55 parts by weight (0.5 mol) of hydroxyethylethylsulphideare added at 20 in 40 minutes and finally 93 .parts by weight (0.5 mol)of diethyldithiophosphoric acid at 60 during 4 hours. The mixture isstirred at 60 for half'an hour, and then extracted with the chloroformand the chloroform solution is Washed first with 5% NaOH solution andthen with water, dried and evaporated.

120 parts by Weight'of a liquid residue are obtained, the refractiveindex 11 of which is 1.5335 and this on distillation yields 115- partsby weight of the pure compound (C H O) PS C H SC H Yield: 84% of thepure product.

If in the above example, the 1 part by volume of sul- -phuric'acid wereomitted under the same conditions, only 67 parts by weight of the samecompound are obtained which corresponds to a yield of 50%.

Example -10 i A mixture of 82 parts by weight (1.1 mol) ofdimethylformamide and 74 parts by weight (0.7 mol) ofhydroxyethylethylsulphide are added drop by drop during 1 hour at 20 to82 parts by weight of 66% oleum (0.67 mol S0 and 0.29 mol H 80 Themixture is then heated .to 60 and-106 parts by weight (0.67 mol) ofdimethyl- Example 11 40 parts by weight (0.4 mol) of sulphuric acid areadded to 62 parts by weight of 66% oleum (0.5 mol S0 and 0.2 mol H 80and then 62 parts by weight (0.85 mol) of dimethylformamide are added at10 to 20 and lastly 53 parts by weight (0.5 mol)hydroxyethylethylsulphide are added. 96 parts by weight (0.5 mol) of asalt of the formula (C H O) PO-SNa are added gradually at 60 during 4hours and then the mixture is stirred for another hour at 60.

After working up thereaction medium as usual, 91 parts by weight of theproduct are obtained, the refractive index m of which is 1.4948 andwhich yields, on

=110 -112; n 9=1.4948. The analysis of the crude product is as follows:'

Calculated: P, 12.01%;

5, 24.03%. Found: 1, Yield: 71% of the pure product.

Example 12 To a mixture of 20 parts by weight (0.2 mol) of concentratedsulphuric acid and 41 parts by weight of 66% oleum (0.33 mol S0 and0.14.mol H 80 a mixture of 37 parts by weight (0.33 mol) ofhydroxyethylethylsulphide and 41 parts by weight (0.55 mol) ofdimethylformamide is added during 1 hour at 20. Then during 4 hours at54.2 parts by weight (0.33 mol) of a salt of the formula (CH O) POSNaare added gradually. The mixture is then stirred for 1 hour at 60, andfinally extracted with chloroform.

42 parts by weight of a liquid with a refractive index n of 1.5095 areobtained which, on distillation yield 40 parts by weight of a mainfraction. B.P. at 0.1 mm. :115 n =1.5O52. The analysis is as follows.

For (Cl-I 0) P O--S C H SC H Calculated: P, 13.4%; S, 27.9%. Found forthe crude product: P, 12.3%; S, 28.2%. Found for the distilled product:P, 13.0%; S, 28.1%. Yield: 55% of the pure compound.

Example 13 61 parts by weight of 65% oleum (:05 mol S0 are added withagitation during 30 minutes to 61 parts by weight of dimethylformamide(DIF) so that the temperature does not rise above 50. To the stilleasily stirred paste so obtained, there are added, drop by drop, during15 minutes 55 parts by weight of hydroxyethylethylsulphide (=05mol+about 4% excess), during which the. temperature should not riseabove 20.

After finishing this operation, the reaction mass is heated to 60 and156 parts by weight of a technical solution of dimethyldithiophosphoricacid in xylene (about 50%=0.5 mol dimethyldithiophosphoric acid) areadded during 3 to 4 hours with agitation. After that, the reactionmixture is cooled to 20 and 100 parts by volume of water and 100 partsby volume of xylene are stirred into it. The lower layer consisting ofdilute sulphuric acid is run off and the upper xylene layer is washedtwice with water, once with 5% caustic soda solution and again withwater.

The bulk of the xylene is distilled off at 50 and at 13 mm. pressure,after whichin order completely to remove .the solvent the reaction flaskis connected to a high vacuum (0.1 mm.) for 1 hour at'50. The residue isconstituted by 121 parts by weight=98% theory. It consists, in the main,of a compound of the formula (CH O) PSSC H SC H and has the followingproperties. n =1.55l2. P found: 12.3%. Calculated'for the above formula:12.6%. S found: 38.7%. Calculated for the above formula: 39.0%. -B.P.107 at 0.02 mm. 111 at 0.06 mm. n of the distilled product: 1.5516.

The paper chromatographic examination showed that the crude product hada degree of purity of at least distillation, 91.5 parts by weight of acompound of the Example 14 7 tion of dimethyldithiophosphorie acid inxylene (about 50%=0.5 mol dimethyldithiophosphoric acid) are added tothe reaction mass withagitation during 3 to 4 hours.

After this, stirring is continued for another 30 minutes'at I 601andthen the contents of the flask are cooled and diluted with parts 'byvolume of water and .200 parts by volume of xylene. This-is worked up asdescribed in properties.

n =l.5526. B.P. 1l0l15 at 0.08 mm. pressure: n of the distilledproduct=l.5513.

The paper chromatographic examination shows a degree of purity of thecrude product of at least 90%.

The expression a fairly low or average temperature 7 as hereinbeforeemployed refers to a temperature within the range from 20 to +30 C.; theexpression a low, normal or raised temperature refers to a temperaturewithin the range from 10 to 70 C.; and the expression ambienttemperature or a raised temperature refers to temperatures within therange of about to above C. (ambient) and within the range from 50 to 70C. (raised).

While hydroxyethylethylsulfide has been used as alcohol II in theforegoing examples because it is the preferred alcohol, it will beunderstood that this alcohol may just as well be replaced by equivalentquantities of other alcohols of Formula H, such e.g. ashydroxyethylphenylsulfide, hydroxyethylbenzylsulfide,hydroxyethyl-methylmercapto-ethylsulfide.

Having thus disclosed the invention, what is claimed 1s:

1. A process for the preparation of an ester of the formula whichcomprises reacting an acid of the formula of such acids and operating insuch a way, that any water of reaction is removed as it is formed, R inthe foregoing formulae being alkyl with 1 to 2 carbon atoms,

and R being a member selected from the group'consisting of uninterruptedalkyl with 1 to 2 carbon atoms, alkylene-O-lower alkyl andalkylene-S-lower alkyl, and Y is a member selected'from the groupconsisting of 0 and S. i

2. A process for the preparation of an ester of the fognula V (monPS-GHZCHf-S-Rg which comprises reacting an acid of the formula V and analcohol of the formula uocu ou sn in the presence of a proton-acid, andoperating in such a way, that water of reaction is removed as it isformed, each of R and R being an alkyl group with a maximumofitwocarbonatoms. I

3. A process for the preparation of an ester of the which comprisesreacting an acid of the formula 'and an alcohol of the formula r'rocucmsn in the presence of a proton-acid, and operating in such a way, thatwater of reaction is removed as it is formed, each of R and R being analkyl group with a, maximum of two carbon atoms.

4. A process according to claim 2, wherein the reaction is carried outin a solvent medium.

5. A process according to claim 4, wherein the solvent medium isdimethylformamide.

6. A process according to claim 2, wherein the firstnamed acid isselected from the group consisting of dimethylthiolphosphoric acid anddiethylthiolphosphoric acid.

7. A process according to claim 6 wherein the alcohol ishydroxyethylethylsulphide.

8. A process according to claim 2, wherein the water of reaction isremoved under reduced pressure.

9. A process according to claim 2, wherein the water of reaction isremoved as an azeotrope.

10. A process according to claim 2, wherein the water of reaction isremoved by a dehydrating agent.

11. A process according to claim 3, wherein the reaction is carried outin a solvent medium.

12. A process according to claim 11, wherein the solvent medium isdimethylformamide.

13. A process according to claim 3, wherein the firstnamed acid isselected from the group consisting of dimethyldithiophosphoric acid anddiethyldithiophosphoric acid.

14. A process according to claim 13, wherein the alcohol ishydroxyethylethylsulphide.

15. A process according to claim 3, wherein the water of reaction isremoved under reduced pressure.

16. A process according to claim 3, wherein the -water of reaction isremoved as an azeotrope. r

17. A process according to claim 3, wherein the water of reaction isremoved by a dehydrating agent.

18. .A process for the preparation of an ester of the formulas-omom-s-n,

which comprises reacting an acid of theformula O (RIO)2P land an alcoholof the formula V 7 I nocn cn sn in the presence of a Lewis acid, andoperating in such a way that waterof reaction is removed as it isformed,

each of R and R being an alkyl group with a maximum of two carbon atoms.l I

19. A process for the preparation of an ester of the formula in thepresence of a Lewis acid, and operating in such a way, that water ofreaction is removed as it is formed, each of R and R being an alkylgroup with a maximum of two carbon atoms.

20. A process for the preparation of an ester of the formula Y (R)2PSCHrCHz-S-R2 which comprises reacting an alkaline salt of an acid of theformula /Y (RtO)zP and an alcohol of the formula nocn cmsn in thepresence of a proton-acid, and operating in such a way, that any Waterof reaction is removed as it is formed, R in the foregoing formulaebeing alkyl with 1 to 2 carbon atoms, and R being a member selected fromthe group consisting of uninterrupted alkyl with atoms, alkylene-O-loweralkyl, and 'alkylene-S-lo'wer alkyl, and-Y is a member selected from thegroup consisting of O and S.

21. A process for the preparation of an ester of the formula Y (R10)2PS-CHnCfiz-S-R:

which comprises reacting an acid of the formula and an alcohol of theformula HOCH CH SR 1 to 2 carbon

1. A PROCESS FOR THE PREPARATION OF AN ESTER OF THE FORMULA